In vitro studies demonstrate that N-demethylation of amitriptyline to nortripty-line is mediated mainly by cytochrome P450-3A4, while hydroxylation of amitripty line to 10-hydroxy-amitriptyline is mediated in part by P450-2D6. This data pre-dicts the possibility of impaired clearance of amitriptyline in vivo by coadmin-istration of ketoconazole or quinidine, highly active and relatively specific competitive inhibitors of 3A4 and 2D6, respectively. This hypothesis will be tested in two prospective double-blind controlled kinetic-dynamic studies.